The curious case of a heterozygous loss-of-function PSEN1 variant associated with early-onset Alzheimer's disease.
BACKGROUND: Over 300 mutations in PSEN1 have been identified as causes of early-onset Alzheimer's disease (EOAD). While these include missense mutations and a few insertions, deletions, or duplications, none result in open reading frame shifts, and all alter γ-secretase function to increase the long/short Aβ ratio. METHODS: We identified a novel heterozygous PSEN1 nonsense variant, c.325A > T, in a patient and his father, both presenting with EOAD, resulting in the substitution of lysine 109 with a premature stop codon at position (p.K109*). This produces a truncated 109 amino acid (aa) N-terminal PSEN1 fragment. Functional characterization was performed using overexpression models and a heterozygous mouse model (Psen1K109*/+). RESULTS: In overexpression models, downstream ATGs serve as alternative starting codons, generating a > 37 kDa and a > 27 kDa PSEN1 C-terminal fragment (PSEN1-CTFA and PSEN1-CTFB, respectively) that retain the two catalytic aspartates of γ-secretase. Heterozygous Psen1K109*/+ mice exhibited subtle phenotypic defects, including reduced Pen2 expression and mild APP-CTF accumulation. Notably, aged mice demonstrated significantly increased Psen2 protein expression, potentially contributing to an elevated Aβ42/Aβ38 ratio. CONCLUSIONS: These findings indicate that PSEN1 c.325A > T (p.K109*) is not a complete loss-of-function mutation. However, to what extent and by what mechanism it contributes to EOAD pathogenesis remains unclear. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-025-00004-x.